IL-4 is a T cell-derived cytokine that regulates the induction of proliferation of resting B cells, and appears to act on various other cells involved in the immune response. The pluripotential effects of IL-4 are dependent on the interaction of IL-4 with its receptor (IL-4R). Although the regulation and metabolism of these receptors have been examined on B and T cells, little is known about the metabolism or regulation of the IL-4R on macrophages. In studying the dynamics of IL-4R expression on the murine macrophage-like cell line J774.16, we detected the presence of low numbers of high affinity IL-4R (234 +/- 38, Kd = 110 +/- 11 pM) on the surface membrane. However, upon exposure to IFN-gamma, a potent macrophage activating cytokine, there was a rapid upregulation (within 45 min) of IL-4R (2750 +/- 178) on the cell surface, with no change in receptor affinity (Kd = 205 +/- 37 pM). Maximum expression occurred at 2 to 4 h with no further increase in IL-4R expression over the next 48 h. Cells pulsed with IFN-gamma for 45 min displayed maximum IL-4R expression by 4 h. The induction of IL-4R by IFN-gamma was dose dependent: as little as 0.5 ng/ml of IFN-gamma was capable of inducing IL-4R expression, with optimal induction at 10 ng/ml. The addition of the metabolic inhibitors actinomycin D and cycloheximide before the addition of IFN-gamma indicated that both RNA transcription and protein translation were required for this upregulation to occur.